A Cross Sectional study to assess olfactory function and quality of life changes in patients with allergic rhinitis before and after medical therapy

A CROSS SECTIONAL STUDY TO ASSESS OLFACTORY FUNCTION AND QUALITY OF LIFE CHANGES IN PATIENTS WITH ALLERGIC RHINITIS BEFORE AND AFTER MEDICAL THERAPY

A dissertation submitted to the Tamil Nadu Dr. M. G. R. Medical University, Chennai in

partial fulfilment of the requirement for the MS Otorhinolaryngology (Branch IV)

A CROSS SECTIONAL STUDY TO ASSESS OLFACTORY FUNCTION AND QUALITY OF LIFE CHANGES IN PATIENTS WITH ALLERGIC RHINITIS

BEFORE AND AFTER MEDICAL THERAPY

Dissertation submitted to the

THE TAMIL NADU DR. MGR MEDICAL UNIVERSITY, CHENNAI

In partial fulfilment of the requirements for the degree of

MASTER OF SURGERY

IN

OTORHINOLARYNGOLOGY

By

KATTI BLESSI SARA

Register number: 221414353

DEPARTMENT OF OTORHINOLARYNGOLOGY

CHRISTIAN MEDICAL COLLEGE

VELLORE

CERTIFICATE

This is to certify that “A CROSS SECTIONAL STUDY TO ASSESS OLFACTORY

FUNCTION AND QUALITY OF LIFE CHANGES IN PATIENTS WITH ALLERGIC RHINITIS BEFORE AND AFTER MEDICAL THERAPY

” is the bonafide work of Dr. KattiBlessi Sara under my supervision in the Department

of Otorhinolaryngology, Christian Medical College Vellore in partial fulfilment of the

requirements for the M.S ENT Examination Branch IV of the Tamil Nadu Dr. M.G.R

Medial University to be held in April 2017 and no part thereof has been submitted for

any other degree.

Dr. Rupa VedantamMS,DLO

Professor and Head

Department of ENT Unit 3

Christian Medical College&Hospital

Vellore-632004.

CERTIFICATE BY THE HEAD OF THE DEPARTMENT/ PRINCIPAL

This to certify that “A CROSS SECTIONAL STUDY TO ASSESS OLFACTORY

FUNCTION AND QUALITY OF LIFE CHANGES IN PATIENTS WITH ALLERGIC RHINITIS BEFORE AND AFTER MEDICAL THERAPY” is the bonafide work of Dr.KattiBlessi Sara under the supervision of Dr.RupaVedantam,

Professor and head of ENT unit 3 in the Department of ENT, Christian Medical College

Vellore.

Dr.Rita Ruby AnbuselviDr Anna P Pulimood

Professor and Head, Principal

Department of Otorhinolaryngology,Christian Medical College

Christian Medical CollegeVellore.

DECLARATION

I, Katti Blessi Sara, do hereby declare that the dissertation titled “A CROSS

SECTIONAL STUDY TO ASSESS OLFACTORY FUNCTION AND QUALITY OF LIFE CHANGES IN PATIENTS WITH ALLERGIC RHINITIS BEFORE AND AFTER MEDICAL THERAPY” is a genuine record of research done by me under the supervision and guidance of Dr Rupa Vedantam, Professor and head,

Department of ENT-Unit 3, Christian Medical College, Vellore and has not previously

formed the basis of award of any degree, diploma, fellowship or other similar title of

any university or institution.

Vellore Katti Blessi Sara

Acknowledgements

I would like to thank God for giving me this opportunity to study and His divine

providence in helping me to finish this dissertation.

I would like to express my deep gratitude to my esteemed guide and teacher, Professor

and head, Dr. Rupa Vedantam for designing the study, for her constant support,

meticulous guidance without which this dissertation would not have been possible.

I am extremely thankful to Ms. Tunny Sebastian, for all her help in analysing the data

and results.

I would like to thank Dr. Rita Ruby, Professor and head of ENT for her constant support

and words of encouragement.

I would like to thank Dr. Reji Kurien and Dr. Suma Susan for helping me to recruit

their patients in my study and encouraging me to be persistent in my effort.

I would like to thank Dr. Lalee for all her suggestions and help in completing the work

I am very grateful to Dr. Vijay and Dr. Raghav without whose help I would not recruit

the patients in my study.

I am thankful to Professor Juniper for giving me the copy right permission to use the

QOL questionnaire for my study.

I would like to express my thankfulness to Mrs. Bhavani for coordinating the work and

helping me to finish this work.

I would like to thank all my patients for being a part of my study.

I would like to thank Dr.Ebenezer for helping me with the translation of consent forms.

Lastly, I am so thankful to God for my parents, younger brother and younger sister

Esther, for all the technical help and fine tuning my work and continuously cheering me

TITLE

A cross sectional study to assess olfactory function and quality of life changes in

patients with allergic rhinitis before and after medical therapy.

.

DEPARTMENT

Department of Otorhinolaryngology, Christian Medical College, Vellore

NAME OF THE CANDIDATE :KattiBlessi Sara

DEGREE AND SUBJECT : MS ENT

NAME OF THE GUIDE :Dr Rupa Vedantam

BACKGROUND

Allergic rhinitis is a common inflammatory disease prevalent world wide which is

known to affect both olfaction and quality of life. Very little information is available

regarding the impact of medical therapy on these parameters in patient with allergic

rhinitis in the Indian subcontinent.

OBJECTIVES

1)To assess the prevalence of olfactory dysfunction in patients diagnosed with allergic

2) To evaluate associated quality- of –life changes in patients diagnosed with allergic

rhinitis 3) To assess the reversal of olfactory dysfunction and any change in quality –of-life

in affected patients following medical therapy

METHODS

A cross-sectionalhospital based study was conducted prospectively in patients

diagnosed with allergic rhinitis All recruited patients underwent butanol threshold testing for

assessment of olfactory function and assessment of quality of life using a RQLQ questionnaire.

These patients underwent medical therapy with steroidal nasal spray, antihistamines and/ or

leukotriene receptor antagonists for about 8-12 weeks

At the end of therapy, the same tests were administered again. As there is no normative

data for the Indian population, 40 normal individuals were tested to obtain normative

data for olfaction testing.

RESULTS

A total of 150 patients with allergic rhinitis were recruited. Most patients (72%)

had intermittent, mild or moderate allergic rhinitis. Smokers were more likely to have

moderate to severe allergic rhinitis than non-smokers (p=0.01). The prevalence of

hyposmia in patients with allergic rhinitis was 28.7%. The degree of hyposmia was mild

(52.9%) or moderate (35.3%)in the majority. Following therapy, there was a significant

improvement in olfaction scores (p=0.001). Quality of life (QOL)was affected in all

patients with allergic rhinitis and the mean QOL scores were raised, particularly those

significant improvement following therapy (p=0.00)

CONCLUSION

Allergic rhinitis impacts both olfaction and quality of life in Indian patients.

The problem is more pronounced in smokers. With adequate medical therapy which

includes a steroid nasal spray, antihistamine and leukotriene anatagonist, most patients

Contents

ABSTRACT ... 13

TITLE ... 17

Introduction ... 22

Aims & Objectives ... 25

Review of the literature ... 27

ANATOMY and PHYSIOLOGY ... 28

Chemosensory elements in humans ... 29

Histology of olfactory epithelium ... 30

Embryology of Olfaction ... 32

Olfactory pathway... 33

Theories of Olfaction ... 34

Central Pathway for olfaction ... 35

Effect of olfaction with ageing and in disease ... 36

Tests of olfaction ... 37

Allergic rhinitis ... 38

Pathophysiology of sinonasal allergy ... 39

1.Sensitization ... 39

2. Early Phase Response ... 42

3. Late phase response ... 44

SYSTEMIC ACTIVATION ... 48

Clinical manifestations of sinonasal allergy ... 48

Effect of olfaction in allergic rhinitis ... 49

Diagnosis of allergy ... 51

Classification of allergic rhinitis ... 52

Quality of life in sinonasal allergy ... 53

Therapeutic Options in Sinonasal allergy ... 55

Histamine ... 55

ANTIHISTAMINES ... 58

Studies showing the efficacy of antihistamines in allergic rhinitis ... 63

INTRANASAL STEROIDS ... 65

Effect of treatment of allergy on olfaction ... 69

Materials and methods ... 71

Chemosensation, which includes the sensations of both smell and taste, is an

important aspect of the sensory system in human beings. It involves the transduction of

chemicals into sensations. Olfaction is the special sense mediated by sensory cells

located in the olfactory area of the nasal cavity. One of the prime uses of the sense of

olfaction in human beings is that it is helps to act as a surveillance system which

detects the hazards in the environment. The other functions of the olfactory system

include generating feelings of pleasure, promoting adequate nutrition, influencing

sexuality and influencing mood. Any cause of dysfunction could potentially be a

source of emotional distress to the patient(2).

The sensation of olfaction may be affected by various physiological and

pathological conditions. Some of the physiological conditions that can affect the

sensation of smell include age, puberty and pregnancy. A decreased sense of smell may

be associated with certain nasal conditions like allergic rhinitis, atrophic rhinitis and

sinonasal polyposis. Head trauma can sever the olfactory rootlets and cause anosmia.

Tumours of the nasal cavity including olfactory neuroblastoma , a tumour arising from

olfactory epithelium cause anosmia. Various neurodegenerative conditions can

diminish olfaction. A number of air-borne and water borne toxins can damage olfactory

epithelium. Atrophy of the olfactory bulb may be present even at birth or secondary to

an acquired disease leading to anosmia.

In the present study we have aimed to study the degree of affectation of the

with sneezing, watery nasal discharge, nasal obstruction, epiphora and heaviness of the

head. Additionally, patients with allergic rhinitis often complain of decreased smell

sensation. Objective assessment may reveal affectation to a variable degree, however.

Very often, however, the sensation of smell is restored with appropriate therapy of nasal

allergy. Some patients, however, do not recover completely.

In order to study the impact of allergic rhinitis on olfaction, we aim to present the

results of subjective and objective assessment of the olfactory system in patients with

allergic rhinitis both before and after initiation of therapy. Simultaneously, we will also

AIM

A cross sectional study to assess olfactory function and quality of life changes in

patients with allergic rhinitis before and after medical therapy.

OBJECTIVES

1) To assess the prevalence of olfactory dysfunction in patients diagnosed with allergic

rhinitis

2) To evaluate associated quality- of –life changes in patients diagnosed with allergic rhinitis

3) To assess the reversal of olfactory dysfunction and any change in quality –of-life in affected

ANATOMY and PHYSIOLOGY

The nose is an important sense organ in the body and it performs two main functions. It

acts both as a respiratory passage and organ of smell.

The nasal cavity extends from the nostrils to the posterior nasal apertures and is sub

divided into right and left halves by the nasal septum. Each half has a roof, floor, and

medial and lateral walls. Each half measures 5 cm in height, 5-7 cm in length, and

1.5cm in width near the floor. The width near the roof is only 1-2 mm. The nasal septum

is a median osseocartilaginous partition between the two halves of the nasal cavity. The

sensory nerve supply of the nasal septum is mainly derived from trigeminal nerve. The

superior part of the septum is supplied by the internal nasal

branch of the anterior ethmoidal nerve. The posteroinferior part is supplied by the

nasopalatine branch of the pterygopalatine ganglion. Special sensory nerves or

olfactory nerves are confined to the upper part or olfactory area(3).

Olfactory area in humans

This is an area located approximately 7 cm from the anterior end of the nasal cavity

in the roof. It is approximately 1 square centimetre in area and includes the

cribriform plate and adjacent areas of the septum and lateral wall of the nose.This

area can be distinguished from the rest of the nasal mucosa because of its yellow

Chemosensory elements in humans

Human chemosensation comprises of 4 distinct elements.

1.Nervus terminalis..

This has been identified as terminal nerve system which is called as cranial nerve

zero(5).

2.Main olfactory nerve i.e. olfactory nerve

3.Vomeronasal or accessory olfactory system

Olfactory nerve which is the first cranial nerve mediates the sense of smell and

the perception of flavour. This nerve innervates the olfactory epithelium which is

present at the cribriform area(6).

Free nerve endings of the trigeminal nerve which is the fifth cranial nerve

innervates the entire nasal cavity. The nerve endings are sensitive to irritation, burning ,

cooling and tickling sensations. The odorants which are in high concentration stimulate

these nerve endings and they initiate reflexes which increase secretions from nasal

mucous glands, halts the inhalation of potentially noxious and harmful substances

which can damage the lower airway. Cranial nerve zero which has been described in all

the vertebrates including humans comprises of a loose plexus of nerve fibres in the

nasal cavity. These nerves are identified with their nodal points which are present at the

end of these nerve fibres(7).

Histology of olfactory epithelium

Olfactory epithelium which lines the nasal cavity serves the special purpose of

olfaction. It is a pseudostratified columnar epithelium and it contains olfactory

receptors beneath the cribriform plate in the nasal vault. Olfactory epithelium

consists of 4 different types of cells which are olfactory cells, supporting cells, basal

cells and brush cells. Olfactory mucosa is histologically made of three layers, epithelial

layer,basal lamina and lamina propria which adheres to the underlying bone or

Olfactory cells

These cells consist of the cell bodies of bipolar neurons which

aggregate to form the olfactory nerve. The nerve fibres pierce the cribriform plate

and terminate on the dendrites of mitral cells lying in the glomeruli of the olfactory

bulb. The apical poles of the neurons are covered with non motile cilia and they have

olfactory receptors. These receptors contain odorant binding proteins which are

dissolved in the secretions of the Bowman’s glands. The process of dissolving of these

proteins in the secretions of Bowman’s glands is essential for the process of olfaction.

Supporting cells

and act as metabolic and physical support for the olfactory cells(8). The nuclei of

these cells is more apical than the epithelial cells

Basal Cells

These cells lie on the basal lamina of the lining epithelium. These are stem cells

which are capable of division and differentiation into either a supporting cell or

olfactory cell. This constant division causes olfactory epithelium to be replaced in every

2-4 weeks. These cells can be of two types: horizontal basal cells which lines the

olfactory epithelium and more superficial globose basal cells(9).

Brush cells

These are columnar cells which bear microvilli and help in transduction for general

sensation. The nerve fibres are terminal branches of trigeminal nerve. These act as

afferents for non- olfactory signals

Bowmans glands

Bowman’s glands are tubuloalveolar glands located in the lamina propria

of the olfactory epithelium which secrete mucus. These glands are also called olfactory

glands. They deliver a proteinaceous substance to the surface of the mucosa. These

secretions trap and dissolve odorants and present them to the bipolar neurons. Old odors

are washed away by the constant flow from these glands(10).

Embryology of Olfaction

differentiates to form olfactory placodes. Invagination of the central part of olfactory

placodes forms the olfactory sac. The olfactory sac opens anteriorly and the olfactory

organ is the only organ in the body where the cell bodies lie in direct contact with

external environment.

Olfactory pathway

The olfactory pathway can be broadly divided into a peripheral system which

receives the odorant stimuli and a central pathway that processes the stimulus so

generated. The olfactory nerve, like the optic nerve, is considered as part of the central

nervous system, however.

Upto 10- 20 million olfactory cells are present in the nasal mucosa and the cell

bodies of these cells act as primary olfactory receptor neurons(ORN). The proximal end

of the ORN which has unmyelinated axons joins to form myelinated fibres which are

called fila olfactoria. There are about 15- 20 foramina in the cribriform plate.The

olfactory fila pass through the cribriform plate to synapse in the olfactory bulb. As the

pathway is short which communicates the nasal cavity with the central nervous system,

there is a higher chances of damage in this pathway and higher risk of spread of

infection from the nasal cavity to the central nervous system.

The olfactory cilia project down into the mucous layer which is rich in lipids. This

mucous is secreted by Bowmans glands which resides in the olfactory epithelium and

helps in transporting the odorant molecules which interact with the olfactory receptors

Above the mucus layer rests the base of the olfactory epithelium which has basal

cells which divide through mitosis which later form the olfactory receptor neurons and

the turnover of these neurons is 40 days. The receptor neurons has pigmented cells

which are light yellow in humans and the depth of the colour correlates with olfactory

sensitivity

Theories of Olfaction

The steric theory of Odour

Linus Pauling in 1946, illustrated that the specific odour quality is due to the

molecular shape and size of the odor molecule.He suggested that the chemical

molecules which are air borne are smelt only when they fit into the specific receptor

sites. This was like a lock and key mechanism. This receptor is then activated and

couples the G-protein and the signal transduction cascade begins.

The vibrational theory of olfaction

Dyson suggested this theory which states that the vibration of a specific

molecule is associated with odour. This validity of this theory did not last after 1970 as

there were different enantiomers (molecules which are not mirror images of each other)

which were described which have same spectrum in the infra red zone but smelt

Central Pathway for olfaction

Olfactory receptor neurons extend to contact odorants in the atmosphere on

one side of the cribriform plate of ethmoid, while on the opposite side the neuronal

cells bundle to form groups which penetrate the cribriform plate, reaching the olfactory

bulb where they converge. In the olfactory bulb a complex coding and decoding process

occurs before the signals are sent to various parts of the central nervous system. The

detection of odorants starts with a sniff causing turbulent airflow , odorant dissolving

into the mucosa which are transported by chaperons which are the transport molecules

to the specific odorant binding protein, thus producing the olfactory signal. The second

method in olfaction is retrograde, whereby the odorants which arise from the

nasopharynx ascend into the choana, thus reaching the olfactory epithelium.This is an

important pathway for the perception of the flavour of the food. The olfactory

epithelium is provided with myelinated fibres from the trigeminal nerve. The distal

fibres of the trigeminal nerve are between the supporting cells under the epithelial

surface and here they are unmyelinated. They respond to sensory stimuli. After leaving

the olfactory bulb, the second order neurons form the olfactory tract. This tract passes

along the base of the frontal lobe and enters in a complex pattern in the pyriform cortex,

anterior commisure, caudate nucleus, olfactory tubercle, and anterior limbus of the

internal capsule with secondary connections. Here it reaches the olfactory cortex where

Effect of olfaction with ageing and in disease

Olfaction can be disrupted in various diseases. There is perceptual interweaving of the

odour and taste. There is also replacement of the olfactory epithelium with respiratory

epithelium and loss of bulb neurons as age progresses .

Causes of smell impairment

Intranasal airway obstruction

• Trauma

• Edema

o Allergic, including polyps and vasomotor rhinitis

o Inflammatory ededma

• Exudates

• Neoplasms

• Atrophic rhinitis

• Ageing (mucosal replacement)

• Viral infections

• Toxic chemicals and drugs

Head trauma

• Fracture of the cribriform plate

• Shearing laceration of the olfactory nerves

• Haemorrhage causing intereference with frontal lobes, olfactory bulbs or tracts

Intracranial lesions

Endocrine

• Kallmans syndrome

• Turners syndrome

Psychiatric problems

Tests of olfaction

There are various tests to assess olfactory dysfunction in patients. The tests include the

Sniffin’ sticks test(11), UPSIT(University of Pennsylvania Smell Identification test)(12)

and CCCRC test(Connecticut Chemosensory Clinical Research Centre)(13). The

CCCRC test which is widely used consists of 3 components, viz., threshold testing

using butanol, odour identification and odour discrimination. In the butanol threshold

Each nostril is tested separately. The point of transition between no detection of smell to

identification of smell is considered as the threshold for that individual. Based on the

results of the 3 components of the CCCRC test, a composite score is calculated. A

diagnosis of anosmia, hyposmia and normosmia may be made, depending on the

composite score obtained. As the CCCRC test is easy to perform and can be

administered within a few minutes, it is the preferred test for assessment of olfaction.

Allergic rhinitis

Allergic rhinitis is a disorder of the nose induced after the exposure to allergen. This is

due to IgE mediated inflammation of the membranes lining of the nose(15). The

three cardinal symptoms affecting the nose in allergy are sneezing, nasal obstruction

and mucous discharge. Allergic rhinitis is a global health problem and a major illness

causing disability with a prevalence of . Patients from different countries, different

ethnic groups and different ages suffer from this. Allergic rhinitis affects social life,

work and scholastic performance. The economic burden of the disease is always

underestimated(16).

Allergic rhinitis is an inflammation of the lining of the nose and is characterized by

anterior or posterior watery rhinorrhoea, sneezing, nasal blockage and itching

of the nose wherein the symptoms occur on 2 or more consecutive days for more than

one hour on most days. There may be associated ocular symptoms(17).

It is the most common form of non- infectious rhinitis.There is a marked increase

continuous with that of the paranasal sinus mucosa, congestion of the ostia can result in

inflammation and obstruction to the paranasal sinuses.

Pathophysiology of sinonasal allergy

The pathophysiology of allergy is a complex process which involves cell mediators,

chemokines, neuropeptides and adhesion molecules.It is a type 1 hypersensitivity

reaction. The reaction is considered in 4 phases.

1. Sensitization

2. Early phase reaction: subsequent reaction to allergen

3. Late phase reaction

4. Systemic activation

1.Sensitization

Allergens are harmless molecules which do not elicit symptoms in non atopic

individuals. Every allergen has an antigenic epitope which is that part of the allergen

that is the antigenic determinant which is recognised by antibodies, T cells or B cells.

It is that specific region of the allergen where the antibody or immune cell binds. In

individuals who are sensitive, these allergens are not completely cleared by the

mucociliary system and are presented to Langerhans cells and dendritic cells which are

mucosa. These cells contain Birbeck granules which increase in number on exposure to

allergen. The activation of these antigen presenting cells is very important for the

activation of T lymphocytes which are located in the local lymph nodes. The epithelial

surface of the human nasal mucosa has the highest network of thedendritic cells

numbering > 500 per mm3.The epitopes of the allergen are presented by the antigen

presenting cells to the T cell lymphocytes in the local lymph nodes. The

majorhistocompatibility complex (MHC) is a set of cell surface proteins which the

epitopes of the allergens, bind to them and display them on the cell surface for

recognition by T cells. In humans, the MHC is also called human leucocyte antigen

(HLA).Th 2 cells are lymphocytes which are a subset of T cells present in local lymph

nodes which are produced by activated T cell lymphocytes. The stimulation of Th2 cells

produces cytokines. The activated Th2 cells then stimulate B cells which also

recognise the allergen through its epitope and MHC. The activated recognize B

lymphocytes in the local tissues are stimulated toproliferate, form plasma cells and

Once Ig E is produced, it is specifically taken up by the mast cells. The IgE which then

circulates in the blood stream then recognises the epitope of the allergen every time it

is exposed to it. The patient is thus sensitized and responds to subsequent contact with

2. Early Phase Response

The release of histamines, cytokines and prostaglandins in nasal mucosa cause

allergic symptoms like sneezing, rhinorrhoea and itching. These symptoms occur

within minutes of release of these mediators and are associated with them. When an

allergen is cross linked with an IgE, and this complex is attached to the mast cells, there

is degranulation of the mast cells and all the mediators for allergen response are

released. These mediators can be released from mast cells or from the arachidonic acid

on the cell membrane of the mast cells. Histamine is the most important mediator which

causes symptoms of allergic rhinitis. Its action on the sensory nerve endings causes

itching and sneezing. Its action on endothelial cells causes vasodilatation, plasma

exudation and oedema. Histamine acts directly on the mucous cells on the ipsilateral

side and on the contralateral side of the nasal cavity it acts through neural reflex.

reflexes. Histamine acts as the most important mediator in the early phase and to a

limited extent in late phase by acting on the basophil cells. It also has pro inflammatory

and immune modulatory properties. It increases the production of IL-6 and IL-8 by

activation of vascular endothelial cells with consequent cytokine production. PG D2

(prostaglandin) is the predominant prostanoids which is released.

role in asthma and rhinitis. This includes sulphidopeptide leukotriene which belongs to

the family of eicasonoids generated by lipoxygenase pathway. These increases the

vascular permeability and causes edema in the nose and recruits eosinophils and

neutrophils. Kinins may also be involved in allergic rhinitis, in early and late phases.

These are generated from plasma proteins by the action of kininogen. Kinins are found

in nasal secretions following allergic response and are found to cause rhinorrhoea,

sneezing, obstruction and pain. Preformed mediators are released by degranulation of

the mast cells which include Th2 cytokines such as IL-4, IL-5, IL-13, and

proinflammatory cytokines such as IL-6, IL-8, IL-I0 and TNF-alpha. The release of Th2

cells is very important in the regulation of IgE response. The number of mast cells

usually increase in the nasal mucosa during episodes of seasonal allergy.

3. Late phase response

If high doses of allergen is used there is a late phase response in around 50 %of the

individuals. This is primarily an inflammatory response and includes variety of cells

like macrophages, eosinophils, basophils, mast cells, T cells and neutrophils into the

local reaction site. Late phase response causes nasal obstruction and hyperactivity.

INFLAMMATORY CELLS AND THEIR REGULATION IN ALLERGIC RHINITS

MAST CELLS

In allergic rhinitis patients, mast cells are found to be in abundance in the nasal mucosal

epithelial compartment. Mast cells play the central role in mechanism of allergic rhinitis.

Iranietal(19) described two types of mast cells depending upon the type of proteases

allergic rhinitis, MC (T) type of mast cells are seen. Mast cells release mast cell

mediators and a variety of cytokines like IL- 4, IL-10. IL-6, IL-13. Mast cells causes

extra cellular matrix interaction which up regulate the cytokine production. This

mechanism helps in mast cell activation even when the concentration of antigen is very

low in the environment. Mast cell induces Ig-E synthesis in B cells and activate IgE-IgE

receptor cascade. Therefore mast cells act as the mediator for immediate response and

also as an immune regulator for the ongoing inflammation process both in intermediate

and late phase reactions.

BASOPHILS

Basophils are found in the nasal secretion of patients in

allergic rhinitis. They also play an important role in allergic inflammation. They are

usually not present in peripheral cells and hence not seen in any of the nasal epithelial

cells. The number of basophils relate with the severity of the disease. They release

histamine and cytokines like IL-4 and IL-3 and they are primarily concerned with late

phase recation

EOSINOPHILS

In any chronic allergic disease, eosinophils have an important role to play. They are

derived from a progenitor cell CD34+. These cells will either develop as eosinophils or

basophils. Eosinophils havebilobed nucleus and they are orange coloured cells. They

Their concentration is highest in nasal secretions. Eosinophilic Cell Protein is the major

constituent of nasal secretions. In the tissue , cytokines like IL-5 keep eosinophils alive

for several days by overcoming programmed cell death. Then eosinophils are matured.

These mature eosinophils contain MBP, ECP and eosinophil derived neurotoxin and

eosinophil peroxidise. They synthesize and release cytokines such as IL-3, IL-5,

proinflammatory cytokines that play an important role in the late phase.Wang etal

studied ECP in nasal secretions of 18 atopic patients and 10 healthy volunteers.

Allergen challenge in these atopics induced an increase in eosinophils that persisted for

10 h and was less at 24 h, whereas levels of ECP in these atopics peaked at 24 h

indicating possible degranulation.

T LYMPHOCYTES

They are among the principal factors that regulate the allergic immune

response in allergic rhinitis. Th1 cells predominantly release IFN- gamma and IL-2

and they are primarily responsible for the delayed hypersensitivity. Th 2 cells are

responsible for IgE release and allergic response. Inflammation of the mucosa is

characterized by infiltration of T lymphocytes both in mucosa and sub mucosa. This

causes a cascade increase in all the cytokines which regulate the allergic response and

induces IgEsynthesis by B cells

MACROPHAGES

Allergic reactions occur in a mucosal environment that is rich in both

lower and upper airways, as alveolar macrophages form more than 90% of the cell

population in bronchial alveolar lavage , but airway macrophages on the nasal epithelial

surface just account for about 1 to 2% of the cells. Still, in seasonal and perennial

allergic rhinitis, a significant increase in macrophages has also been found in the

nose .Langerhans cells represent an important group of dendritic cells in the nose,

characterised by the expression of CD1 and Birbeckgranules . These cells increase after

allergen challenge or in patients with allergic rhinitis and may serve as antigen

presenting cells in the upper airway.

EPITHELIAL CELLS

Epithelial cells are present in the mucosa of the nasal epithelium.

Their primary action is about secretion of mucus and removal of foreign body by the

action of their cilia. They also have a wide range of immunomodulatory activity by the

release of eicasnoids, endopeptidases, chemokines and cytokines. Itis now appreciated

that allergens, on account of their enzymatic proteolytic activity can directly activate

cells . House dust mite allergens have been shown to activate epithelial cells in

vitro,inducing cytokine and chemokine release and thus can induce airway inflammation independent of IgE. It has also been shown that epithelial cells in allergic

individuals are more sensitive to air pollutants like diesel exhaust particles and this has

been attributed to the greater constitutive and pollutant induced release of

ONGOING INFLAMMATORY PROCESS

Structural cells like epithelial cells, residential cells like mast cells and the infiltrated

inflammatory cells like eosinophils, basophils and T cells all play a role in inducing

and maintaining on-going allergic inflammation. While cytokines like IL-4, and IL-13

released from mast cells and T cells help drive B cells toward IgE synthesis and could

contribute to the local IgE synthesis in the nasal mucosa of patients with allergic rhinitis

SYSTEMIC ACTIVATION

Allergic Rhinitis is not just associated with local

response but also a systemic response. This response helps us to explain the link

between the patients who have rhinitis and asthma. In patients with AR without asthma

produces inflammatory response in both the upper and lower airway and increased

bronchial activity. In sensitized individuals, allergen exposure causes a release of many

inflammatory cells and few cells migrate to bone marrow and this recruits the

inflammatory cells like eosinophils and basophils to the target organs.

Clinical manifestations of sinonasal allergy

It is a recently recognised that allergic rhinitis symptoms include more than the classical

watery rhinorrhoea, sneezing and nasal block. It is associated with the impairment of

day to day life of individuals.There is a significant impairment in the quality of life of

social and emotional impairment of the normal function of the individuals(21). Poor

control of the symptoms has a significant impact on the sleep pattern.

There is a genenral impairment in the overall function of the individual at work or at

school(22). The severity of the allergic rhinitis is based on the severity of the

impairment of the normal function of an individual when compared to the other normal

individuals(23).

Effect of olfaction in allergic rhinitis

Allergic rhinitis(AR) is a common inflammatory disease prevalent world wide affecting

10-25% of the population(24). Some studies have shown that the prevalence of

olfactory dysfunction in allergic rhinitis ranges from 21%-23 %(25).Further, olfactory

with perennial AR. There are 2 potential causes for olfactory dysfunction in AR, viz.,

inflammation and obstruction.The degree of blockage is not related to the degree of

olfactory dysfunction. This suggests that olfactory dysfunction is secondary to

inflammatory response which occurs in the nasal cavity(26).

Becker etal have studied olfactory dysfunction using the sniffin’ sticks test in

seasonal and perennial AR and correlated the results with analysis of nasal secretions

and inspiratory rhinomanometry. Of a total of 72 patients, 23 were proven seasonal AR ,

16 were perennial AR and 33 healthy volunteers. The authors concluded that nasal flow

rhinomanometry did not show any significant difference in the three groups. However,

olfactory thresholds were significantly less in the AR group when compared to the

normal control group. Further, there was not much difference in the score between the

seasonal and perennial AR groups. On analyzing the nasal secretions, it was found that

increased levels of eosinophilic cationic protein was present in patients with AR

compared to the control group(27). Guilemany et al studied the impact of sense of smell

in patients with persistent AR. They studied 49 patients with persistent AR and 60

controls. The authors found that there was significant olfactory dysfunction in patients

with persistent AR when compared to the control group.All these patients were positive

for skin allergy test(28).

Some studies have shown that olfactory dysfunction improves in

patients who are treated with intranasal steroids. The mechanism behind this is unclear.

It is possible that reduction of the oedema or inflammation is the cause for this

phenomenon. Other studies have shown a significant reduction in the number of

using the topical steroid mometasonefuroate in a group of patients with AR, the

improvement in inflammation was significantly higher in patients who were

administered mometasonefuroate compared to placebo, showing that inflammation is

significantly reduced in patients using mometasonefuroate(29). Stevens et al studied the

response to topical nasal and oral steroids in patients following endoscopic

polypectomy(30). In this prospective study, 24 patients who were anosmic prior to

endoscopic and nasal surgery, were selected. Most of the patients had either bronchial

asthma or AR or both. Twelve out of 24 remained anosmic postoperatively and did not

respond to either nasal steroids or oral steroids. More patients responded to oral than

topical steroids, however. Alobid et alstudiedthe effect of oral and intra nasal steroids in

severe nasal polyposis. They randomised the patients into two groups after 4 weeks of

steroid washout period. The first group was given 2 weeks of oral steroid followed by

12 weeks of intranasal steroids. The control group which included 22 subjects did not

receive any steroid treatment .Barcelona Smell Test 24 (BAST-24), nasal congestion,

tissue eosinophilia, and nasal nitric oxide were assessed.The authors found that

combined nasal and oral steroids improved olfaction in the cases but not the

controls(31). Very few studies have evaluated the change in olfaction following medical

therapy of AR without polyposis.

Diagnosis of allergy

The diagnosis of Allergic rhinis is based upon the concordance of the history and

diagnostic tests. The typical symptoms include watery nasal discharge, sneezing and

Diagnostic tests include skin allergy test and an increased IgE levels in the blood. Skin

Allergy test which is commonly used is prick and puncture test(32). The modified skin

prick test by Pepys is the current test which is commonly used(33). Negative and

positive controls are used in this test. Negative control consists of the diluents which are

used to preserve the allergen vaccine(34). A rare dermographic patient can produce

wheal and flare to the diluents which are used(35). Positive control is used to detremine

the supression by medication and the technique of administartion of the test. The usual

positive control which is used is histamine dichloride (36)

Classification of allergic rhinitis

Mild

 Normal Sleep

 Normal daily activities

 Normal Work and School

 No troublesome

symptoms

Intermittent symptoms  ≤4 days per week  Or ≤ 4 weeks

Persistent symptoms

 4 days per week and > 4

weeks

Moderate-Severe One or More Items

 Abnormal sleep

 Impairment of daily

activities sports, leisure

 Problems cause at school or

work

Quality of life in sinonasal allergy

Allergic rhinitis causes impairment in the performance of daily functions by

patients thus affecting the quality of life both in children and adults. Patients can also

suffer from sleep disorders, emotional problems and imapirment in routine social

activity and social functioning.

Olfactory function is an important component of quality of life (QOL) and mental

health in patients with sinonasal disease(37). Various indicators have been used to

assess the quality of life in patients with sinonasal disease. These include SF-36

QOL(short form health survey), SNOT 22(sino nasal outcome test), ESPRINT 15.

RSDI(rhinosinusitis disability index), RQLQ (rhinoconjuctivitis and quality of life) and

HRQL (health related quality of life). SF -36 is a generic QOL instrument which does

not specifically address olfaction or allergy(38). In contrast, the ESPRINT-15

(short-form instrument to measure health-related quality of life in adults suffering from

allergic rhinitis) questionnaire, which was first developed and validated on a Spanish

population, is unique in that it assesses QOL in patients with allergic rhinitis(39). The

instrument contains 15 items covering 5 domains, viz. Symptoms (5 items), daily

activities(3 items), sleep (3 items), psychological affectation(3 items) and wellness (1

item). Items are scored using a 6 point Likert scale, ranging from 0 to 6. In a study on

patients with mild, moderate and severe AR, Valeroetalfound that there were significant

differences in the global score and individual scores of ESPRINT QOL between the

various categories. Juniperetalhave designed RQLQ questionnaire to assess the

quality of life in patients with rhinoconjunctivitis with or without allergic in origin. This

in 7 domains (activity limitation, sleep problems, nose symptoms, eye symptoms,

non-nose/eye symptoms, practical problems and emotional function). There are 3

‘patient-specific’ questions in the activity domain which allow patients to select 3

activities in which they are most limited by their rhinoconjunctivitis. Patients recall how

bothered they have been by their rhinoconjunctivitis during the previous week and to

respond to each question on a 7-point scale (0 = not impaired at all - 6 = severely

impaired). The overall RQLQ score is the mean of all 28 responses and the individual

domain scores are the means of the items in those domains.

A number of studies have shown improvement in QOL after

therapy in patients with AR. Mir etal in their review have concluded that the burden of

AR on school going children and the impact of it on their quality of life is significant .

They have also found that intranasal corticosteroids have been the best treatment in AR

thus far .Canonica et alhave studied the effect of quality of life in AR. They used an

online survey and telephonic interview of 3635 people with AR. The authors found that

many patients have poor quality of life secondary to AR .Kalpiagolu et alsimilarly

evaluated the quality of life in patients with asthma and AR and a combination of

both.They studied a total of 316 patients out of which 232 had AR, 40 had asthma and

44 had both diseases. The authors used the SF 36 and HRQL questionnaire to assess the

quality of life. They found that AR has a minor role on quality of life. Juniper et al

validated and developed a questionnaire to assess the quality of life in children with

rhinoconjunctivitis.The authors developed a questionnaire which was accurate and

used to assess QOL in patients with AR.

Therapeutic Options in Sinonasal allergy

Histamine

Pharmacology

The biogenic amine, histamine acts as a major mediator for inflammation and

anaphylaxis and gastric acid secretion and a major role in neurotransmission. It acts

through 4 classes of receptors

Chemical structure

It’s a hydrophilic molecule consists of an imidazole ring and an amino

group. These two rings are connected by two methylene groups. The pharmacologically

active form of the histamine is the monocationic form. H3 and H4 receptors have a

higher affinity that H1 and H2. The four receptors can be activated by any nalogue of

histamine.

Distribution and Biosynthesis of Histamine

Histamine is present in almost all the mammalian tissue ranging from <1

to >100microgm. The mast cell is the predominant storage site for the histamine in most

tissues. The concentration is high in those cells where mast cells are high like skin,

bronchial mucosa and intestinal mucosa.

Synthesis, storage and Metabolism

Its formed by the decarboxylation of the amino acid histidine by the enzyme

L-Histidine decarboxylase. This enzyme is present in the every mammalian tissue that

blood. These cells store histamine in secretory granules and they have the ability to

synthesize histamine. Non mast cells sites of histamine formation consists of gastric

mucosa, epidermis and neurons within the CNS. Turnover is rapid at the non mast cell

site as the histamine is not stored but released continuosly. There are two major paths of

histamine metabolism in humans. The most important one is ring methylation to form

N-methylhistamine . Most of the N-methyl histamine is then converted to N-methyl

imidazole acid by monamineoxidase(MOA)

Release and functions of endogenous histamine

Histamine plays a central role in immediate hypersensitivity and allergic responses.

As it is released from the storage granules, it interacts with IgE antibody on the mast

cell surface. And thus participates in the entire hypersensitivity response. Histamine has

a major role in neurotransmitter release and also gastric acid secretion.

Role in Allergic Response

The principal target cells of immediate hypersensitivity is mast cells and basophils.

As a part of the allergic response to an antigen. IgE antibodies are generated and bind to

the surface of mast cells and basophils via a receptor. Antigen bridges the IgE

molecule via FceR1 and activates signalling pathways in mast cells and basophils.

Pharmacological Effects

Receptor-effector coupling and mechanisms of action

Histamine receptors are GPCR . H1 receptor is coupled to GQ11 and activate adenylyl

cyclase pathway, where as H3 and H4 receptors inhibit adenylyl cyclase

pathway.Stimulation of H1 receptors on smooth muscle cause contraction, whereas

Histamine Receptors

Ash and Sehild predicted the existence of histamine receptors.

H1 and H2 receptors

These receptors are widely distributed in the peripheral and central nervous

system..Histamine exerts local or wide spread effects on smooth muscles and glands.It

causes itching and stimulation of secretion from nasal mucosa. In lungs it contracts the

bronchial smooth muscles and in gut causes contraction of smooth muscles and apotent

stimulator of gastric acid secretion. Bronchoconstriction and contraction of gut and

nasal mucosal secretion are mediated by H1 receptors. Gastric acid secretion are

mediated by H2 receptors.

H3andH4 receptors

H3 receptors are auto receptors. They inhibit histamine release and modulate releasof

otherneurotransmitters.H3 receptors high constitutive activity, histamine release is

tonically inhibited and inverse agonist will thus reduce receptor activation and increase

histamine release from histaminergic neurons. Therefore H3 agonist promote sleep and

antagonist promote wakefulness.H4 receptors are found in cells of haematogenic

origin like eosinophils, basophils, monocytes and mast cells. Activation of H4 receptors

in these cells induces cellular shape change, chemotaxis , secretion ofcytokines and up

regulation of adhesion molecules. This suggest that, H4 antagonist can be used in

Effect of histamine release on increased capillary permeability

The effect of histamine on small vessels causes efflux of plasma

protein and fluid into extracellular spaces and increases lymph flow thus causing

edema.H1 receptors are the major mediators of this response. Increased permeability is

caused by histamine activation of H1 receptors on post capillary venules. This contracts

the endothelial cells and exposes the basement membrane which is freely permeable to

plasma proteins and fluid.

Triple response of Lewis

Intradermal injection of histamine produces a characteristic response known as the

triple response. This consisits of

• Localised red spot a few millimetres around the site of injection within a few

seconds and reaches its maximum in less than a minute.

• A brighter red ‘flush’ or ‘flare’ extending more than 1cm beyond the red spot

develops more slowly.

• A wheal that is seen within 1-2 minutes occupies the same area as the original

red spot.

Initial red spot results from direct vasodilating effect of histamine, flare is due to

histamine induced stimulation of axon reflexes that causes vasodilation indirectly and

wheal is histamines capacity to increase the capillary permeability

ANTIHISTAMINES

Antihistamine was first described by Bovet and Staub in 1937. The initial substance

colleagues described pyrelamine maleate an effective antihistamine which was used

clinically. In 1980, non sedating antihistamines were developed for the treatment in

allergic responses.

Pharmacological properties Chemistry

All the H1 receptor antagonists are inverse agonists that reduce the constitutive activity

of the receptors and compete with histamine. This causes antihistamine binding to the

receptor thus causing inactive conformation. If a histamine binds to the receptor it

causes active conformation. Like histamine, many of the antihistamines

contain a substituted ethylamine moiety. Unlike histamines it’s a tertiary amino group

linked by 2 or 3 atom chains to two aromatic substances.

Mechanism of action

Immediate hypersensitivity reactions : Anaphylaxis and allergy

Histamine is the most potent autocoid released in hypersensitivity reactions. The

symptoms ensuing its contributions varies from species to species. Therefore the

protection offered by H1 antagonist also varies from species to species. In humans,

itching and edema formation are well suppressed, however its effect on blood pressure

is not very marked.

Capillary permeability

H1 antagonists block increased capillary permeability ,edema and wheal caused by

histamine. H1 antagonists suppress the action of histamine on nerve endings, thus

Classification of antihistamines

Antihistamines which are used in allergic rhinitis belong to H1 antagonist group

These drugs are classified into classified into first and second generation antihistamines

primarily based on the ability to cross the blood –brain barrier. The second generation

antihistamines primarily act on the peripheral H1 receptors and have a reduced ability to

cross the blood brain barrier. They are thus less sedating in action. The drugs included

in these 2 classes are seen in the table .The differences between the 2 classes of

antihistamines is also listed .

First generation antihistamines

• Tricyclic dibenzoxipens

• Ethanaloamines

• Ethylenediamines

• Alkylamines

• Piperazines

• Phenothiazines

• Piperadines

Second generation antihistamines

• Tricyclic

• Alkylamines

• Piperazines

• Piperadines

Chemical Classification of H1 antihistamine

Alkylamines

Ethanolami

nes

Ethylenediam

ines

Phenothiazi

nes

Piperazin

es

Piperidine

s

Antazoline Promethazine Buclizine Azatadine

Chlorpheniramin e

Clemastine Tripelennamine Trimeprazine Cyclizine Cyprohepta

dine Dexchlorphenira

mine

Dimenhydrin ate

Pyrilamine Mequitazine Meclizine Ketotifen

Pheniramine Diphenhydra

mine

Oxtamide Loratadine

Dimethindene Doxylamine Hydroxyzi

ne

Desloratadi ne

Triprolidine Phenyltoxami

ne

Cetirizine Bilastine

First-Generation H1 antihistamines Second-Generation H1 antihistamines

Usually administered in three to four daily

doses

Usually administered once or twice a day

Cross the blood-brain barrier (lipophilicity ,

low molecular weight, lack of recognition

by the P-glycoprotein efflux pump)

Do not cross the blood-brain barrier

(lipophilicity , high molecular weight,

recognition by the P-glycoprotein efflux

pump)

Potentially cause side-effects

(sedation/insomnia/hyperactivity/convulsio

ns)

Do not cause relevant side-effects

(sedation/fatigue/hyperactivity/convulsio

ns)

Case reports of toxicity are regularly

published

No reports of serious toxicity

No randomized, double-blind,

placebo-controlled trails in children

Some randomized, double-blind,

placebo-controlled trails in children

Lethal dose identified for infants/young

children

Do not cause fatality in overdose

Therapeutic uses of antihistamines

H1 antagonists play an important role in the symptomatic treatment of various

immediate hypersensitivity reactions.

H1 antagonists are most useful in acute allergic reactions with symptoms of rhinitis,

urticaria and conjunctivitis. These drugs are treated for seasonal allergic rhinitis and

conjunctivitis. They relieve the symptoms of sneezing, rhinorrhoea and itching of nose

and throat. These drugs are used for acute phase of symptoms. They are not effective of

chronic phase of symptoms.

Adverse effects

The most important adverse effect is sedation. The next important side effect is loss of

appetite, nausea, vomiting, epigastric pain, constipation and diarrhoea. Owing to the

antimuscarinic actions there are effects like dryness of throat, mouth and respiratory

passages.

Antihistamines used in Allergic rhinitis

Cetrizine

It is a second generation piperazine. It has minimal anticholinergic

effects. It has also negligible penetration into the brain but is associated with a higher

incidence of drowsiness. The active enantiomer levocetrizine is more potent and less

drowsy when compared to that of the first genetation drugs.

Fexofenidine

This drug is a second generation piperadine. They are highly selective H1 receptors.

They lack significant anti cholinergic actions and penetrate poorly into the CNS.

Studies showing the efficacy of antihistamines in allergic rhinitis

study, for 2 weeks, in patients with seasonal allergic rhinitis. The first week of the study

was an open label period where all the patients received fexofenadine 60 mg twice daily.

A small number (25-33%) of patients had persistent symptoms. These patients(334)

were divided into 3 categories. The first group received only azelastine nasal spray, the

second group received azelastine with fexofenidineandthe third group received placebo

nasal spray each for 1 week of duration. The authors concluded that those patients who

were administered azelastine nasal spray as monotherapy as well as those given

fexofenidine and azelastine nasal spray together responded well for seasonal allergic

rhinitis and showed no difference in their response.(41)Those patients that received

placebo nasal spray showed

Berkowitz etalanalysed the results of two studies . These studies were double blinded

randomized controlled studies which compared the effect of fexofenifine and

pseudoephedrine with a placebo in seasonal allergic rhinitis. These studies recorded

allergic rhinitis symptoms for 2 hours after dosing and 30 minute interval for 4 hours.

The primary end point was the onset of action which was measured in the symptom

score. The secondary end point was to include the absolute and total change in the

percent score of the symptoms. A total of 1693 patients were screened in which 786

were randomized. The authors concluded that the patients with fexofenidine had onset

of action at 45 minutes and the effect lasted for a total duration of 6 hours.

(42)Guilemanyetal studied the impact on smell in allergic rhinitis and reversal of the

same after the use of antihistamines. The study group included 27 patients who had

symptoms, endoscopy, skin prick test, acoustic rhinometry, peak nasal inspiratory flow,

nasal nitric oxide and olfactory test (Barcelona smell test) were performed in all patients

with persistent allergic rhinitis at baseline and after 7 days and 30 days of treatment with

levocetrizine 5mg or placebo. The study population was randomized into 2 groups, with

14 receiving levocetrizine and 13 receiving placebo.

The symptoms score after 7 and 30 days were noted. Significant improvement in loss of

smell was observed after 7 days of levocetrizine treatment. This study

concludedthatlevocetrizine was effective against symptoms of persistent allergic

rhinitis and also caused an improvement in the loss of smell. The improvement in

olfaction was believed to be secondary to reduction in nasal inflammation rather than

nasal patency(43).

INTRANASAL STEROIDS

Effect of steroids on inflammatory response Molecular level

The action of the glucocorticoids(GC) begins at the molecular

level when the glucocorticoid crosses the cell membrane and binds to the GC receptor.

These receptors are present in the in the cytoplasm of the cell and are in an inactive form

maintained by heat shock proteins. GC disrupts the heat shock proteins which enables

the diffusion of GC into the nucleus of the cell. GC exerts its anti inflammatory

response using two pathways. The first pathway is transactivation where in the

receptor molecule which binds the GC encodes the anti inflammatory gene. The second

inflammatory response of the cell(44).

Cellular level

GC inhibits the function of the infiltrating inflammatory cells into the nasal mucosa.

GC also inhibits the cytokines and maturation of the mast cells. It inhibits the histamine

release from basophils , enhances the apoptosis of eosinophils and reduces the

recruitment of antigen presenting cells likethe Langerhans cells and dendritic cells. It

also reduces the numbers of Th2 cells. It has also an anti inflammatory effect on nasal

mucosal constituent cells such as epithelial cells, vascular endothelial cells and

fibroblasts(45).

Doses

Intranasal steroids are better than any other drugs in the management of nasal block,

congestion and rhinorrhoea. They exhibit their anti inflammatory effect by inhibiting

production and release of cytokines. They decrease the vascular permeability and down

regulate the secretion of the mucous glands. Their onset of action is slow and the

maximum efficacy develops over weeks and days. In extreme congestion, nasal steroid

will not reach the mucosa and hence a decongestant is used initially and the steroid is

used after that(46). Topical steroids can be used regularly and the usage can be

commenced before the onset of pollen season.

Fluticasone propionate, beclomethasone, mometasone and budesonide are the most

commonly used nasal steroidal sprays used. Fluticasone propionate contains 50 mcg

per spray and the maximum dosage that can be given is 200mcg. Fluticasone furoate

contains 27.5 mcg per spray and the maximum dosage to be given is 110mcg per day.

Beclomethasone contains 42 mcg per spray and a total dose of 168 mcg per day can be

given. Mometasone contains 100mcg per spray and a maximum of 400mcg can be

given per day. Nasal sprays are administered into each nostril at regular intervals as

once daily or twice daily doses.

Side effects

Intra nasal steroids can cause drying of the nose, crusting and resultant epistaxis.

Fluticasone causes a decrease in the endogenous secretion of cortisol but there is no

effect on adrenal suppression. Few studies show that there is a minimal decrease in the

skeletal growth. Sivametal performed a randomized double blinded placebo controlled

parallel clinical trial in 17 patients who had symptoms of impaired olfaction. The

subjects received MometasoneFuroate or placebo for 2 weeks. Nasal peak inspiratory

treatment. Nasal cytology samples were obtained from each visit and the biopsy

specimen of the olfactory epithelium was obtained at the end of the study and was

scored for inflammation. The results of this study showed that the patients on

Mometasonefuroate had improved quality of life, olfaction, nasal symptoms and

inflammation. Histological analysis of the olfactory epithelium showed that there were

fewer eosinophils in patients who received Mometasonefuroate(29). Julliossonsetal

performed a double blinded placebo controlled study of 25 patients with allergic rhinitis

who were administered a 4 week treatment of topical fluticasone. The authors also

studied the relationship between the tissue density of mast cells, tissue histamine levels

and levels of markers of mast cell activation after an allergen challenge of the nasal

mucosa in these patients following therapy with fluticasone. . Nasal biopsies were

obtained before and after treatment. Mast cell density, tryptase levels and tissue

histamine levels were evaluated. At 2 weeks intervals nasal challenges were performed

for 8 weeks. The symptoms of nasal allergy were assessed after each challenge.

Treatment with fluticasone propionate did not influence mast cell density or tissue

histamine concentration. However, there was a reduction in nasal symptoms and

tryptase in nasal lavage. This study showed that measurement of tryptase is an indicator

of both mast cell activation and efficacy of topical steroid treatment(47).

LEUKOTRIENE ANTAGONISTS

Leukotriene antagonists act by inhibitingcysteinyl leukotrienes which are the

important mediators of allergic rhinitis. There are two drugs which come under this

cysteinyl leukotriene receptors(48).

Mechanism of action

Cysteinyl leukotrienes (C4,D4 andE4)cause increased microvascular permeability,

inflammatory cell chemotaxis, mucus secretion and neuronal stimulation and

bronchoconstriction. Compared to histamine, leukotrienes C4 and D4 are 1000 times

more potent as bronchoconstrictors. These drugs are used often singly or in

combination with antihistamines in the therapy of allergic rhinitis.

These drugs are well absorbed orally, highly plasma protein bound and metabolized by

hepatic enzymes like CYP 2C9. The plasma half life of monteleukast is 3-6 hours(49).

Side effects

These drugs have few side effects, like headache and rashes.

Mast cell stabilisers Sodium cromoglycate

This is a synthetic chromone derivative and inhibits the degranuation of the mast

cell. Release of mediators from mast cell is prevented(50).. Long term treatment

reduces the cellular inflammatory response. Sodium cromoglycate is not absorbed

orally. It is administered as an aerosol. It is not a nasal decongestant. But regular usage

as a prophylactic can produce symptomatic improvement in patients.

Effect of treatment of allergy on olfaction

The medical treatment of Allergic Rhinitis includes predominantly intranasal

corticosteroids , antihistamines and leukotriene antagonists. Corticosteroids have a

Allergic Rhinitis. At the local site they cause membrane stabilisation and alteration in

the release of mediators and inhibits the migration of cells. This mechanism is helpful in

the restoration of the olfactory functiom at the olfactory mucosa. The advantage of

using a steroid nasal spray is that high drug concentration is provided at the target

receptor site and there is a minimum risk of side effects. Wober etal assessed the effect

of azelastine in 211 children less than 13 years of age. These childern were treated with

Azelastine nasal spary for 2 weeks. There was a significant reduction in the symptoms

of these children who were treated with sprays. The olfaction has significantly

improved from 72.1% to 94.6%(51). Gamberdella etal has compared in a randomized

control study the effect of loratidine tablet with azelastine nasal spray. They have not

found a statistically significant difference in the olfactory function of the patients in

both the groups. Meltzer etal assessed the eefcet of treatment with mometasone on 41

individuals for 2 weeks. Olfactory fucnction was assessed with CCCRC test pre and

post treatment. They have found that there was a significant increase in the odour

threshold for the patients when treated with mometasone when compared to that with

placebo(52). In a recent trial of Higaki etal in 2012, have studied the effect of 12

weeks of mometasone versus 4 weeks of placebo and 8 weeks of mometasone, and 12

weeks of placebo during the pollen season. Interstingly, they have found that there was

Study Design:

This is an observational prospective study

Study Population:

All patients who report to the ENT OPD who fit into the ARIA criteria of allergic

rhinitis.

Inclusion Criteria:

• All patients diagnosed with allergic rhinitis

• Patients aged 18 years or greater

• Patients should not have used steroidal nasal sprays at least 2 weeks prior to the

first test

• Patients without degenerative disease, neurological conditions or malignancy or

recent nasal surgery

Exclusion Criteria

• Patients below the age of 18 years

• Patients who has obvious nasal pathology like sinonasal polyps, Gross deviated

nasal septum which is touching the lateral wall of the nose and malignancy

• Patient